Prognostic factors in Epstein-Barr virus-associated stage I-III gastric carcinoma: Implications for a unique type of carcinogenesis

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) has distinct clinicopathological features. However, the prognostic factors remain unclear, particularly in UICC/AJCC stage I-III cancer. We retrospectively enrolled 1,020 patients with stage I-III gastric cancer that received radical gastrectomy with lymphadenectomy. Formalin-fixed, paraffin-embedded surgical specimens were retrieved to construct tissue microarrays. EBV positivity was identified by in situ hybridization with EBV-encoded small RNA, and the histological classification was reviewed. Fifty-two cases of EBVaGC were identified, exhibiting a male predominance (p=0.003), a higher prevalence in stump cancer (p<0.001), and poorly differentiated carcinoma (p=0.010) compared with the controls. The survival analysis revealed no difference in survival between the EBVaGC cases and the EBV-negative cases (p=0.977). The multivariate analysis showed that EBVaGC cases with a tumor size >5 cm, non-lymphoepithelioma-like carcinoma (LELC), or a lymph node ratio >0.15 had a worse overall survival (hazard ratio 2.884, 12.178 and 19.352; p=0.027, 0.005 and <0.0001, respectively). The depth of tumor invasion and the number of lymph node metastases did not reach statistical significance (p=0.834 and 0.833, respectively). These prognostic factors, tumor size, LELC classification and lymph node ratio, may reflect a unique type of carcinogenesis of EBVaGC and may be considered when selecting high-risk patients for adjuvant treatment.